The secretion of renin is the first step in the renin-angiotensin cascade, which plays both physiological and pathophysiological roles in the regulation of arterial blood pressure and in the regulation of the volumes and compositions of the body fluids. The overall aim is to elucidate the actions and mechanisms of action of first messengers controlling renin secretion, the second messengers which mediate the effects, and how these second messengers interact. Evidence suggests that intracellular free ionic Ca (Cai) and cyclic AMP are inhibitory and stimulatory second messengers, respectively. It is proposed to test four hypotheses: (1) that there is a direct relationship between membrane potential and secretory activity of the renin-secreting juxtaglomerular cells, i.e., that inhibitory first messengers depolarize whereas stimulatory first messengers hyperpolarize; (2) that the "Ca channels" opened by high perfusion pressure (inhibitory to renin secretion) are pharmacologically-identical to the "Ca channels" opened by membrane depolarization; (3) that cyclic AMP and Cai are sequentially-acting second messengers, that cyclic AMP stimulates renin secretion by increasing Ca efflux and sequestration, thereby decreasing Cai; (4) that four first messengers (angiotensin II, vasopressin, alpha-adrenergic agonists, A1-adenosine receptor agonists) inhibit renin secretion by increasing Cai, either by (a) inhibiting adenylate cyclase, thereby decreasing Ca efflux and sequestration, or by (b) stimulating phospholipase C, presumably, thereby increasing Ca release from intracellular sequestration sites. A pharmacological approach is proposed. Renal cortical slices and isolated perfused kidneys will be used as the experimental preparations. SIGNIFICANCE: Considering the physiological and pathophysiological roles of the renin-angiotensin- aldosterone axis, understanding the mechanisms controlling renin secretion is of great importance. The results of these experiments will provide new information concerning first and second messengers, and also concerning the mechanisms of action of various substances which are frequently used not only in renin secretory studies, but also in treating cardiovascular diseases (e.g., cardiac glycosides and Ca channel blockers). Finally, elucidation of the role played by Cai in renin secretion has importance with respect to general cellular physiology, since Cai appears to be an inhibitory second messenger in the renin- secreting juxtaglomerular cells, but in nearly every other type of cell, Cai acts as a "trigger," or as a stimulatory second messenger.